Abuse resistant pharmaceutical compositions

ABSTRACT

The present invention relates to a composition comprising pharmaceutical active ingredients which are susceptible to, or have potential for, abuse. The invention provides an oral pharmaceutical composition comprising a first population of beads and a second population of beads. The first bead population comprises a pharmaceutically active ingredient susceptible to, or having the potential for, abuse. The second bead population comprises a gelling agent and a coating substantially surrounding the gelling agent, but containing no pharmaceutically active ingredient. The first bead population and the second bead population are physically separable, but visually indistinguishable to the naked eye. Upon ingress of water into the second population of beads, the gelling agent is caused to swell forming a viscous mass inhibiting or preventing the extraction of the active ingredient.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of and claims priority topending non-provisional U.S. patent application Ser. No. 14/484,761filed on Sep. 12, 2014, which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

The present invention relates to a composition comprising pharmaceuticalactive ingredients which are susceptible to, or have potential for,abuse. The composition of the invention is adapted to be abuse resistantso as to reduce or eliminate such abuse.

BACKGROUND OF THE INVENTION

It is widely known that certain categories of drugs such as analgesics(e.g. opioids), sedatives (e.g. benzodiazepines) and stimulants (e.g.amphetamines) have potential to be misused or abused if they are notused as intended or as prescribed.

In the case of intentional misuse or abuse a person may attempt toextract the active ingredient from the commercial dosage form in orderto concentrate it and take a larger amount than prescribed or to takethe drug in a different manner to that prescribed, the object being toproduce a euphoric “high” or some other pharmacological effect otherthan that produced when the product is used as intended.

One mode of abuse involves crushing a dosage form and inhaling orsnorting the resultant powder. Another mode of abuse involves extractingthe active ingredient with water, alcohol or some other solvent toproduce a liquid form for injection.

As part of a wider effort to address the issue of deliberate misuse orabuse of prescription drugs the US Food and Drug Administration hasissued a draft guidance for industry on abuse-deterrent opioids (see“Guidance for Industry, Abuse-Deterrent Opioids—Evaluation and Labeling,Draft Guidance” US Dept. of Health and Human Services, Food and DrugAdministration, Center for Drug Evaluation and Research, January 2013).The draft guidance provides some background to the problem of opioidabuse and discusses various formulation approaches that may be used inattempts to reduce or mitigate abuse potential. Furthermore, it detailsthe studies, and other requirements, necessary to support labellingwhich contains abuse deterrent or reduction claims.

Various abuse deterrent or abuse reducing approaches are known in theprior art.

U.S. Pat. No. 7,201,920 (Acura Pharmaceuticals, Inc) discloses an abusedeterrent dosage form wherein an active ingredient is combined with apolymer (gel forming agent) to form a matrix. Nasal irritants and/oremetics are also incorporated into the dosage form.

U.S. Pat. No. 7,776,314 (Grunenthal GmbH) discloses a solidadministration form, protected from parenteral abuse and containing atleast one viscosity-increasing agent in addition to one or more activesubstances that have parenteral abuse potential. According to claim 1,the viscosity-increasing agent is present in a quantity equal to orgreater than 5 mg per dosage form and such that an aqueous extractobtained from the dosage form with 10 mL of water at 25° C., forms a gelwhich can still pass through a needle having a diameter of 0.9 mm andremains visually distinguishable when introduced by a needle into afurther quantity of an aqueous liquid.

U.S. Pat. No. 8,529,948 (Purdue Pharma LP) discloses a controlledrelease dosage form comprising a gelling agent in an effective amount toimpart a viscosity unsuitable for parenteral or nasal administration toa solubilized mixture formed when the dosage form is crushed and mixedwith from about 0.5 to about 10 mL of aqueous liquid. The dosage formmay comprise a range of aversive agents (selected from a bitteringagent, an irritant, a gelling agent or a combination thereof) todiscourage an abuser from tampering with the dosage form.

U.S. Pat. No. 8,652,529 (Flamel Technologies) discloses solidmicroparticulate oral pharmaceutical forms having a coating layer whichassures modified release of the active principle and simultaneouslyimparts crushing resistance to the coated particles so as to avoidmisuse.

It is an object of the present invention to provide an oralpharmaceutical composition which is adapted to reduce or mitigatepotential abuse by making it more difficult for the pharmaceuticalactive ingredient to be extracted and used or administered in a mannerother than that originally intended.

It is another object of the invention to provide a pharmaceuticalcomposition which is adapted to reduce or mitigate potential abusewhilst at the same time not compromising the pharmacokineticcharacteristics of the composition.

It is a further object of the invention to provide an abuse resistantpharmaceutical composition which goes at least some way to addressingthe drawbacks of the prior art.

BRIEF DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides an oral pharmaceuticalcomposition comprising a first population of beads and a secondpopulation of beads; said first bead population comprising apharmaceutically active ingredient susceptible to, or having thepotential for, abuse; and said second bead population containing nopharmaceutically active ingredient comprising a gelling agent and apermeable or semi-permeable coating.

The composition is adapted to ensure that the gelling agent contained inthe second bead population, upon contact with water or some otherliquid, forms a uniform, viscous mass. This may be achieved by means ofa permeable or semi-permeable coating which restricts, but does notcompletely prevent, the ingress of water into the gellingagent-containing beads. The coating may be pH independent or pHdependent. Preferably the coating is a pH independent, semi-permeablecoating.

Preferably said first bead population and said second bead populationare physically separable, but visually indistinguishable to the nakedeye.

Whilst the different populations of beads are physically separable, theyshould be indistinguishable in order to thwart attempts to isolate thedrug containing beads. To that end the beads of the first and secondbead populations should be visually indistinguishable to the naked eyein terms of their size, shape and colour etc. Furthermore, the differentbeads preferably have similar densities.

As set out in greater detail below, when the gelling agent present inthe second population of beads is exposed to, or comes in contact with,a liquid such as water, an aqueous material or the like, it is caused toswell. The composition of the invention is designed such that theswelling of the gelling agent does not result in the formation of largesemi-solid lumps which may get lodged in the gastrointestinal tract,thus restricting or prevent passage of the dosage form and the activeingredient contained therein. Rather the composition of the invention isadapted to ensure that swelling of the gelling agent gives rise to amore dispersed, relatively uniform, but viscous mass. As described ingreater details below, this has the effect of isolating or sequesteringthe other constituents of the composition, thus reducing or preventingextraction of the active ingredient.

The composition of the present invention has a number of advantages.Firstly, the coating of the gelling agent-containing second beadpopulation provides a physically robust abuse deterrent component whichmay be readily processed into a final dosage form i.e. mixing andblending of the different populations of beads—an importantconsideration from a manufacturing perspective. Second, when thecomposition of the invention is taken as intended—i.e. withoutmanipulation of or tampering with the composition as prepared—thepresence of the second bead population has minimal or substantially noeffect on the delivery of the pharmaceutically active ingredient. Inother words pharmacokinetic characteristics of the composition of theinvention are substantially the same as those of a similar compositionin which the second bead population is not present—i.e. compositionswith and without the second bead population should be bioequivalent.Third, the coating on the gelling agent-containing second beadpopulation is adapted to make it more difficult to extract the activeingredient using either small or large volumes of a solvent, such aswater.

Because the second bead population embodying the abuse deterrentmechanism is physically distinct from the active ingredient containingbeads, and because there is no interaction between the gelling agent andthe active ingredient-containing beads until the composition isadministered, or an attempt is made to tamper with the composition, thepresent invention lends itself to the incorporation of essentially anypharmaceutically active ingredient which may benefit from an abusedeterrent or tamper mitigating presentation.

The pharmaceutically active ingredient may be selected from the groupconsisting of: alfentanil, allylprodine, alphaprodine, amphetamines(e.g., amphetamine, lisdexamphetamine, methamphetamine,methylenedioxymethamphetamine, dextroamphetamine or methylamphetamine),ephedrine, anileridine, benzodiazepines (e.g., bretazenil, clonazepam,cloxazolam, clorazepate, diazepam, fludiazepam, flutoprazepam,lorazepam, midazolam, nimetazepam, nitrazepam, phenazepam, temazepam orclobazam), benzylmorphine, bezitramide, buprenorphine, butorphanol,carfentanil, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diacetylmorphine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,diphenoxylate, dioxaphetyl butyrate, diprenorphine, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone,hydromorphone, β-hydroxy-3-methylfentanyl, hydroxypethidine,isomethadone, ketobemidone, levo-α-acetylmethadol, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, methylphenidate, metopon, morphine, myrophine, nalmefene,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, o-methylnaltrexone, opium,oxycodone, oxymorphone, papaveretum, pentazocine, pethidine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, propranolol, promedol, properidine,propoxyphene, remifentanil, sufentanil, tilidine, and tramadol, orpharmaceutically acceptable salts, solvates, ester prodrugs, carboxamideprodrugs, derivatives or active metabolites of any of the foregoing or amixture thereof.

In one embodiment, the pharmaceutically active ingredient comprises anopioid. When the active ingredient is an opioid it is preferablyselected from the group consisting of: buprenorphine, butorphanol,codeine, etorphine, fentanyl, hydrocodone, hydromorphone, morphine,oxycodone, or oxymorphone or a pharmaceutically acceptable salt, esterprodrug, carboxamide prodrug, derivative or active metabolite thereof,or a mixture of the foregoing.

In a further embodiment, the pharmaceutically active ingredient is ap-opioid agonist or a pharmaceutically acceptable salt, prodrug(especially an ester prodrug or carboxamide prodrug), derivative oractive metabolite thereof. In another embodiment, the pharmaceuticallyactive ingredient is a full p-opioid agonist or a pharmaceuticallyacceptable salt, prodrug (especially an ester prodrug or carboxamideprodrug), derivative or active metabolite thereof. In anotherembodiment, the pharmaceutically active ingredient is a partial p-opioidagonist or a pharmaceutically acceptable salt, prodrug (especially anester prodrug or carboxamide prodrug), derivative or active metabolitethereof. In another embodiment, the full p-opioid agonist is a morphinanderivative. In another embodiment, the partial p-opioid agonist is amorphinan derivative. In another embodiment, the full p-opioid agonistis a benzomorphan derivative. In another embodiment, the partialp-opioid agonist is a benzomorphan derivative.

In another embodiment, the pharmaceutically active ingredient ishydrocodone or a pharmaceutically acceptable salt thereof. In anotherembodiment, the pharmaceutically active ingredient is17-(cyclobutylmethyl)-4,14-dihydroxy-6-oxo-morphinan-3-carboxamide or apharmaceutically acceptable salt thereof. In another embodiment, thepharmaceutically active ingredient is(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamideor a pharmaceutically acceptable salt thereof.

Gelling agents suitable for use in the present invention include gelforming polymeric materials which swell upon contact with or absorptionof a solvent, such as water, alcohol or some aqueous liquid, thusforming a viscous mass. The increase in viscosity in the vicinity of oraround the first (drug-containing) bead population makes it difficult,if not impossible, to separate the active ingredient-containing beads orto extract the drug substance from said beads.

Gelling agents suitable for use in the composition of the presentinvention include hydrophilic cellulosic polymers, polyethylene oxide(PEO) of various molecular weights (for example having an averagemolecular weight of from about 2,500,000 to about 7,500,000 Daltons),carbomers (polymers of acrylic acid cross-linked with polyalkenyl ethersof sugars or polyalcohols) of various grades and the like. Preferablythe gelling agent comprises a polymer selected from the group consistingof hydroxypropyl cellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene oxide, sodium carboxymethyl cellulose, sodiumalginate and carrageenan. The gelling agent may alternatively oradditionally comprise a gum. Suitable gums include for example xanthangum, guar gum, locust bean gum, gellan gum and glucomannan. The gellingagent may suitably be present in any amount that causes the compositionto gel upon exposure to water. The amount of gelling agent presentshould be such that it does not cause handling problems, such asclogging of coating, encapsulation or tableting equipment. Where thecomposition is presented in a capsule the gelling agent may be presentin amount of at least about 15% (w/w) of the combined dry weight ofactive ingredient(s) and excipients present (in other words 15% (w/w) ofthe overall dry weight of composition), or at least 30 mg per capsule.

The gelling agent-containing beads may further comprise a binder, suchas hydroxypropyl cellulose, hydroxymethylpropyl cellulose, polyvinylpyrrolidone or the like.

The coating applied to the gelling agent serves a number of functions.First, it provides a physical barrier essentially separating orsequestering the gelling agent from the other components of thecomposition, namely the drug-containing first bead population. Secondly,and most important in the context of the abuse deterrent object of theinvention, it serves to control (i.e. delay or otherwise limit) theingress of water into the second bead population, thus restraining thegelling action of the gelling agent.

The coating applied to the gelling agent beads is a coating that ispermeable or semi-permeable to water. The coating may be pH dependent orpH independent. Alternatively the coating may comprise a mixture of pHdependent and pH independent materials. Preferably the coating is a pHindependent, semi-permeable coating.

Suitable coating materials include cellulosic polymers, such ascellulose acetates, cellulose alkanylates and cellulose acrylates;polyamides; polyurethanes; sulfonated polystyrenes; ammonio methacrylatecopolymers such as poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1(for example those sold under the trade name Eurdgit® RS(EvonikIndustries AG); and methacrylic acid copolymers such aspoly(methacrylic acid-co-ethyl acrylate) 1:1 (those sold under the tradename (Eudragit® L(Evonik Industries AG)). Preferably the coatingcomprises an ammonio methacrylate copolymer or a methacrylic acidcopolymer or a mixture thereof. The coating may further compriseplasticizers, pore forming agents, anti-adherents or other excipientsthat enhance the functioning or application of the coating.

The level of coating applied to the beads can be characterised in termsof weight gain (i.e. the gain in weight of the beads followingapplication of the coating) or in terms of coating thickness. Thecoating may suitably be present in an amount of about 5% to about 50%polymer weight gain (i.e. polymer weight added expressed as a percent ofthe weight of uncoated beads; excluding weight of any excipients addedwith the polymer). When the coating comprises an ammonio methacrylatecopolymer or a methacrylic acid copolymer the coating is preferablyapplied to a polymer weight gain of from about 7.5% to about 25%.Preferably the coating will have a thickness from about 1 to about 100μm (microns). When the coating comprises an ammonio methacrylatecopolymer or a methacrylic acid copolymer the coating is preferablyapplied to a thickness of about 10 to about 50 μm.

In one preferred embodiment the pharmaceutically active ingredient ishydrocodone, or a pharmaceutically acceptable salt thereof, the gellingagent is polyethylene oxide and the coating applied to the gellingagent-containing beads comprises an ammonio methacrylate copolymer, amethacrylic acid copolymer or a mixture of an ammonio methacrylatecopolymer and a methacrylic acid copolymer.

An oral pharmaceutical composition may comprise a first population ofbeads and a second population of beads; said first bead populationcomprising a pharmaceutically active ingredient selected from the groupconsisting of hydrocodone and pharmaceutically acceptable salts thereof;and said second bead population, comprising polyethylene oxide and asemi-permeable coating selected from the group consisting of an ammoniomethacrylate copolymer, a methacrylic acid copolymer and mixturesthereof, wherein said second bead population is substantially free ofany pharmaceutically active ingredient. Preferably the polyethyleneoxide is present in particulate form. The composition second beadpopulation may further comprise povidone.

In one preferred embodiment, an oral pharmaceutical composition maycomprise a population of immediate release hydrocodone bitartrate beads,a population of controlled release hydrocodone bitartrate beads and apopulation of gelling agent-containing beads; said gellingagent-containing beads comprising polyethylene oxide (preferably appliedin powder or particulate form), povidone and a semi-permeable coatingselected from the group consisting of an ammonio methacrylate copolymer,a methacrylic acid copolymer and mixtures thereof. Preferably thepovidone is present in particulate form. Preferably the immediaterelease beads contain from 1 to 75% w/w of the total amount ofhydrocodone bitartrate in the composition with the controlled releasebeads containing from 25 to 99% w/w of the total amount of hydrocodonebitartrate in the composition.

Also provided is a pharmaceutical dosage form comprising a compositionof the invention as described above. The composition may suitably befilled into capsules to produce a finished dosage form. Capsules may besoft or hard capsules of any size or shape. Suitable capsules includefor example spherical or elliptical soft elastic capsules; starch,cellulose or gelatin hard capsules (such as Coni-snap® (Capusgel BelgiumNV)) and the like. Appropriate capsules sizes may be selected based onthe number and size of the beads to be incorporated into the dosageform, and include capsule sizes 000, 00EL, 0EL, 0, 1, 2, 3, 4, and 5.Alternatively, the composition of the invention may be compressed intotablet form, filled directly into a sachet or presented in some otherdosage form suitable for oral administration. Preferably a unit dosageform according to the invention comprises at least about 20 mg ofgelling agent per unit (i.e. per capsule or per tablet) and morepreferably at least about 30 mg of gelling agent per unit

An oral capsule dosage form may contain a composition made up ofhydrocodone bitartrate beads and gelling agent-containing beads; saidgelling agent-containing beads consisting essentially of sugar spheres,polyethylene oxide, povidone and a semi-permeable coating comprising apolymer selected from the group consisting of an ammonio methacrylatecopolymer, a methacrylic acid copolymer and a combination thereof. Thegelling agent-containing beads may consist essentially of

(i) sugar spheres 25.0-35.0% w/w (ii) polyethylene oxide 40.0-50.0% w/w(iii) povidone  2.5-7.5% w/w (iv) ammonio methacrylate copolymer 5.0-20.0% w/w (v) silicon dioxide  1.0-7.5% w/w (vi) talc  1.0-7.5%w/w.

In one exemplary dosage form the hydrocodone bitartrate beads consist ofhydrocodone bitartrate immediate release beads and hydrocodonebitartrate controlled release beads filled into a capsule with gellingagent containing-beads. The overall composition may consist essentiallyof

(i) hydrocodone bitartrate 5.0-50.0 mg/capsule (ii) sugar spheres65.0-250.0 mg/capsule  (iii) hypromellose 2.0-15.0 mg/capsule (iv)ammonio methacrylate copolymer 7.5-40.0 mg/capsule (v) silicon dioxide2.5-25.0 mg/capsule (vi) talc  1.0-7.5 mg/capsule (vii) polyethyleneoxide 30.0-100.0 mg/capsule  (vii) povidone 2.5-12.5 mg/capsuleand wherein 20% of the hydrocodone bitartrate are present in theimmediate release beads and 80% of the hydrocodone bitartrate arepresent in the controlled release beads.

Also provided are methods of treating a subject with a pharmaceuticallyactive ingredient susceptible to, or having the potential for, abuse,comprising the step of administering to a subject in need thereof apharmaceutically effective amount of a composition or a unit dosage formof the invention as described above. Where the pharmaceutically activeingredient present in the composition is an analgesic the inventionprovides methods of treating, preventing, reducing or otherwise managingpain, said method comprising administering to a subject in need thereofan analgesically effective amount of a composition or unit dosage formas described above. Preferably said analgesically effective amount isfrom 5 to 250 mg per unit dosage form.

The invention also provides a process for the manufacture of abusedeterrent beads comprising the steps of applying gelling agent particlesand a binder solution, if present, to a substrate to form uncoatedgelling agent-containing beads, and coating said gellingagent-containing beads with a water permeable or semi-permeable coating.Preferably the gelling agent particles comprise polyethylene oxidepowder and a binder solution of polyvinyl pyrrolidone dissolved in anisopropyl alcohol/water mixture comprising from 10 to 30% w/w water.Preferably the PEO powder and the binder solution are simultaneouslyapplied to the substrate to form the uncoated gelling agent beads.

Abuse deterrent beads prepared according to the foregoing process may befilled into capsules with active ingredient-containing beads orcompressed into tablets to form an abuse resistant dosage form.

In a further aspect the invention provides a gelling agent compositionsuitable for imparting abuse resistant character to a compositioncomprising a pharmaceutically active ingredient which is susceptible to,or has potential for, abuse, said gelling agent composition comprising aplurality of beads comprising a gelling agent coated with a permeable orsemi-permeable coating. Suitable gelling agent compositions aredescribed in detail below. The gelling agent may be polyethylene oxide,preferably applied to a substrate in particulate form along with abinder.

DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a gelling agent-containing,abuse deterrent bead according to the invention.

FIG. 2 is a graph illustrating the in vitro release of drug from twocompositions of the invention compared to that of two comparatorcompositions which do not contain a gelling agent component.

FIG. 3 is a graph illustrating the in vivo release of drug (mean plasmaconcentrations) from a composition according to the invention comparedto that of a comparator composition which does not contain a gellingagent component.

FIG. 4 depicts is a graph illustrating the in vivo release of drug (meanplasma concentrations) from another composition of the inventioncompared to that of a comparator composition which does not contain agelling agent component.

FIG. 5A depicts the gelling effect of a hydrocodone bitartratecomposition of the invention upon mixing with various amounts of water(1, 2 & 5 mL).

FIG. 5B depicts the gelling effect of a hydrocodone bitartratecomposition of the invention upon mixing with 1 mL of water and theimpact on ability to syringe the viscous mass produced.

FIG. 6A depicts the initial behaviour of a hydrocodone bitartratecomposition of the invention (20 mg strength) in water (100 mL).

FIG. 6B depicts the composition shown in FIG. 6A after one hour.

FIG. 7A depicts the initial behaviour of hydrocodone bitartratecompositions of the invention (50 mg strength) in water (100 or 200 mL).FIG. 7B depicts the compositions shown in FIG. 7A after one hour.

FIG. 8A depicts a comparative example showing the behaviour of a priorart oxycodone tablet (30 mg) comprising a gelling agent in water (100mL).

FIG. 8B depicts a comparative example showing the behaviour of a priorart oxycodone tablet (80 mg) comprising a gelling agent in water (100mL).

FIG. 9 is a graph illustrating the extraction of drug substance fromhydrocodone bitartrate compositions of the invention compared to priorart oxycodone compositions.

DETAILED DESCRIPTION OF THE INVENTION

The term “bead” as used herein means a discrete unit such as a particle,particulate, pellet, granule or the like, and the terms “population ofbeads” and “bead population” each mean a plurality (two or more) of saidbeads.

The term “gel” as used herein means a three dimensional network orstructure formed from a synthetic and/or natural polymer which canabsorb and retain a significant amount of water (relative to the amountof polymer) upon exposure to an aqueous environment. Gels areessentially dilute cross-linked systems which may be classified as‘weak’ or ‘strong’ depending on their flow behaviour at steady state(weak—meaning more free flowing or relatively less viscous;strong—meaning less free flowing or relatively more viscous). The term“gelling agent” is construed accordingly as a material which forms, oris capable of forming, a gel upon hydration.

The term “permeable” as used herein means the ability of a coating toallow another substance, particularly water or other solvents, to passthrough it. The term “semi-permeable” as used herein means a coatingwith selective permeability, allowing some substances (such as solvents)to pass through it, whilst not allowing the passage of others(especially solutes). Permeable coatings are taken to includesemi-permeable and porous (having interstices or passages that enableliquid to pass though) coatings. By contrast, the term “impermeable” asused herein means a coating which does not allow other substances topass through it.

The term “pH dependent” as used herein means a parameter which varieswith pH (for example, a coating which only dissolves or is onlypermeable within a particular pH range). By contrast, the term“pH-independent” as used herein means a parameter which does not varyaccording to pH (for example, a coating material which exhibits similarpermeability characteristics irrespective of the pH of it surroundingenvironment).

The terms “pharmaceutically active ingredient”, “active ingredient” and“drug” (used interchangeably) as used herein each means a substancethat, when administered to a subject, produces a discerniblephysiological or pharmacological effect. “Pharmaceutically activeingredient” is taken to include prodrugs which, although not directlyactive in terms of producing a physiological or pharmacological effect,do give rise to such effects following transformation, within the bodyof a subject, into an active moiety. Pharmaceutically active ingredientsare distinguished from inactive components or excipients which may playa role in the manufacture of, and/or release of active ingredient from,the composition of the invention, but do not elicit any physiological orpharmacological effect when the composition is administered to asubject.

The term “powder” as used herein means a subdivided solid, typicallycategorised by reference to the size and/or shape of the constituentparticles. For the purposes of the present invention substantially allof the particles of a powder pass through a 10 mesh sieve (i.e. having asieve opening size of 2 mm (2,000 μm).

The term “prodrug” as used herein means a chemical derivative of a drugmolecule (a pharmaceutically active ingredient) that undergoes ametabolic transformation within the body of a subject thus releasing theactive moiety. The term “ester prodrug” is construed accordingly as aninactive ester form (i.e. —CO—OR; where R is an organic substituent), ofa pharmaceutically active ingredient which undergoes transformation,such as hydrolysis, within the body of a subject to release the activedrug. The term “carboxamide prodrug” means an inactive form of apharmaceutically active ingredient bound to an —NRR′ moiety via acarbonyl group (i.e. —CO—NRR′; where R and R′ are either the same ordifferent and are hydrogen or an organic substituent).

The present invention provides an oral pharmaceutical compositioncomprising a first population of beads and a second population of beads;said first bead population comprising a pharmaceutically activeingredient susceptible to, or having the potential for, abuse; and saidsecond bead population comprising a gelling agent and a permeable orsemi-permeable coating substantially surrounding the gelling agent, butcontaining no pharmaceutically active ingredient.

The second bead population comprises a coated gelling agent whichbehaves differently depending on how the composition is handled and/orused. When the gelling agent-containing beads are being processed into afinished dosage form the gelling agent is kept physically separated fromthe external environment by virtue of the coating. This hinders theingress of ambient moisture and means that the gelling agent-containingbeads remain robust. During the manufacture/processing phase it isimportant that the gelling agent is not activated (i.e. that it is notcaused to swell or gel) so as to avoid handling difficulties, such asclogging equipment.

The composition of the invention is intended to be administered orally.When the composition is administered intact and as intended the variousbeads disperse along a region of gastrointestinal tract. Water from thesurrounding environment is absorbed through the coating of the gellingagent-containing beads which, upon contact with the gelling agent,causes the beads to swell. The beads may swell to the extent that thecoating ruptures, thus allowing more rapid ingress of water. Thisgelling action causes the formation of a viscous mass in and around thevicinity of the beads. However, since the gelling agent is presented ina plurality of beads which spread out within the gastrointestinal tract(as opposed to being a monolithic form, such as a tablet) the gellingagent does not produce a localised mass or lump which may get stuck orcause a blockage. Dispersal of the gelling agent-containing beads inthis manner means that the viscous mass produced upon administration ofthe composition of the invention is not localised to the extent that itmight interfere with in vivo release of the drug from the activeingredient-containing beads.

On the other hand, if the composition of the invention is tampered withthe gelling agent inhibits or prevents efforts to extract the drugsubstance. For example, adding the composition to a small volume ofwater causes the gelling agent to gel as described above. In this case aviscous mass which cannot syringed is formed. Furthermore, any drugsubstance dissolved in the water or present as intact beads cannot bedecanted or filtered off because of the viscous nature of the massformed. Any attempt to extract the drug substance that involves crushingthe composition followed by the addition of water or some other solventleads to a similar outcome wherein the active ingredient becomes boundup in a viscous mass that cannot be injected or separated from the drug.

Thus upon ingress of water into the second population of beads thegelling agent is caused to swell forming a gel or viscous massinhibiting or preventing extraction of the active ingredient from thecomposition—unless the composition is administered as intended, in whichcase the action of the gelling agent does not impact release of thedrug. There are a number of specific features which highlight thedifferences between the composition of the invention and prior artcompositions. Compositions of the invention exhibit a gelling behaviourwhen added to water, even in the absence of any tampering i.e. thecomposition behaves the same whether the gelling agent-containing beadsare added to water intact or are crushed first. On the other hand,surprisingly the presence of the gelling agent-containing beads does nothave any adverse effect on the release of drug from the composition andits subsequent bioavailability. Certain prior art compositionscompletely isolate the gelling agent such that it performs no functionat all unless the dosage form is tampered with, and specifically, unlessan attempt is made to crush the dosage form. In contrast, in the case ofthe present invention the gelling agent performs an important role inmitigating or preventing extraction of the active ingredient even if thecomposition is not crushed. Certain prior art compositions are presentedin the form of a tablet in which the active ingredient is intimatelymixed with the gelling agent. This approach has a number ofdisadvantages: first, there may be compatibility issues between the drugsubstance and the gelling agent; secondly, the presence of the gellingagent in such a configuration will inevitably alter the pharmacokineticcharacteristics of the composition; and thirdly, the presentation of thegelling agent in the form of a monolithic mass can retard its ability todisperse, thus reducing its effectiveness as an abuse mitigant.Compatibility is not an issue for the present invention because theactive pharmaceutical ingredient and the gelling agent are physicallyremoved from each other—being present in separate bead populations. Thephysical separation of the active ingredient and the gelling agent alsomeans that the release of drug is not impacted by the presence of thegelling agent component. Furthermore, the presentation of the gellingagent in composition of the present invention results in superiorperformance in terms of the dispersal of the gelling agent, and theformation of a diffuse viscous material, once contacted with a liquid,and in terms of inhibiting the extraction of active ingredient. Thegelling action of the composition of the invention produces a diffusegel of substantially uniform viscosity even in relatively large volumes(e.g. up to about 200 mL). This contrasts with some prior artcompositions where a localised gel may be formed, leaving a supernatantportion where the viscosity may remain substantially unchanged—this hasthe drawback of enabling some of the active ingredient to be extractedfrom the supernatant.

Preferably the pharmaceutically active ingredient is selected from thegroup consisting of: alfentanil, allylprodine, alphaprodine,amphetamines (e.g., amphetamine, lisdexamphetamine, methamphetamine,methylenedioxymethamphetamine, dextroamphetamine or methylamphetamine),ephedrine, anileridine, benzodiazepines (e.g., bretazenil, clonazepam,cloxazolam, clorazepate, diazepam, fludiazepam, flutoprazepam,lorazepam, midazolam, nimetazepam, nitrazepam, phenazepam, temazepam orclobazam), benzylmorphine, bezitramide, buprenorphine, butorphanol,carfentanil, clonitazene, codeine, desomorphine, dextromoramide,dezocine, diacetylmorphine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,diphenoxylate, dioxaphetyl butyrate, diprenorphine, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone,hydromorphone, β-hydroxy-3-methylfentanyl, hydroxypethidine,isomethadone, ketobemidone, levo-α-acetylmethadol, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, methylphenidate, metopon, morphine, myrophine, nalmefene,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, o-methylnaltrexone, opium,oxycodone, oxymorphone, papaveretum, pentazocine, pethidine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, propranolol, promedol, properidine,propoxyphene, remifentanil, sufentanil, tilidine, and tramadol, orpharmaceutically acceptable salts, solvates, prodrugs, derivatives oractive metabolites of any of the foregoing or a mixture thereof.

Particularly preferred active ingredients are those selected from thegroup consisting of: buprenorphine, butorphanol, codeine, etorphine,fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, oroxymorphone or a pharmaceutically acceptable salt, prodrug, derivativeor active metabolite thereof or a mixture thereof. Hydrocodone andpharmaceutically acceptable salts thereof, such as hydrocodonebitartrate, are especially preferred active ingredients because of theabuse potential of these compounds.

Further preferred active ingredients are those selected from the groupconsisting of17-(cyclobutylmethyl)-4,14-dihydroxy-6-oxo-morphinan-3-carboxamide andits pharmaceutically acceptable salts.

Other preferred active ingredients are those selected from the groupconsisting of(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamideand its pharmaceutically acceptable salts.

In the case of chiral compounds the active ingredient may be present asa single enantiomer or as a mixture of enantiomers.

The abuse deterrent bead population (i.e. that comprising the gellingagent) of the composition is inactive in the sense that should containno pharmaceutically active ingredient. The beads comprise a gellingagent core coated with a permeable or semi-permeable coating. In otherwords, the coating applied to the gelling agent beads represents aphysical barrier which is somewhat permeable to water or other solvents.In the case of a pH independent, semi-permeable coating the functioningof the coating is not substantially affected by changes in pH.

The distinct and separable nature of individual gelling agent-containingbeads means that the gelling agent is not confined in a relativelylarge, monolithic form—as is the case with a tablet. As a result the gelor viscous mass formed upon exposure of the composition of the inventionto water (or some other solvent) is more dispersed or diffuse withsubstantially consistent viscosity compared that formed in the case of agelling agent-containing tablet, where the formation of a gel may berelatively localised and limited to a relatively thin layer around theexposed surface(s). The more dispersed, diffuse nature of the gel formedwith the present invention arises because of (i) the greater surfacearea of gelling material exposed in the beads of the invention comparedto a monolithic tablet; and (ii) the readily accessible nature of thegelling agent. The permeable or semi-permeable nature of the coatingmeans that the gelling agent-containing beads will absorb at least somewater irrespective of whether or not the composition has been tamperedwith. The formation of a gel in and around the composition helps tofrustrate attempts to extract the active ingredient from thecomposition, whether in crushed form or intact. This contrasts with someprior art compositions in which a gelling component is only exposed whenthe dosage form is crushed or tampered with in some way.

Another advantage of the composition of the invention is the distinctand separable nature of the active ingredient beads, on one hand, andthe gelling agent beads, on the other. This means that there is nodirect physical interaction between the pharmaceutically activeingredient and the gelling agent. Thus any chemical incompatibilitybetween the two is mitigated. Furthermore, this separation of the activeingredient and the gelling agent means that there is no detrimentaleffect on the release and/or bioavailability of the active ingredient—anissue which can arise where the active ingredient and a gelling agentare present in an intimate mixture.

Gelling agents suitable for use in the present invention include gelforming polymeric materials which swell upon contact with or absorptionof a solvent, such as water, alcohol or some aqueous liquid, thusforming a viscous substance. The gel formed upon hydration of the gelagent may be a strong gel or a weak gel. The formation of such a gel orviscous mass in the vicinity of or around the first (drug-containing)bead population makes it difficult, if not impossible, to separate theactive ingredient-containing beads or to extract the drug substance fromthe composition, particularly where the active ingredient is present inthe form of controlled release beads. Gelling agents suitable for use inthe composition of the present invention include hydrophilic cellulosicpolymers, polyethylene oxide of various molecular weights (for examplehaving an average molecule weight in the range of from about 100,000 toabout 10,000,000 Daltons, preferably within the range of from 750,000 to7,500,000 Daltons), carbomers (polymers of acrylic acid cross-linkedwith polyalkenyl ethers of sugars or polyalcohols) of various grades;gums such as xanthan gum, guar gum, locust bean gum, gellan gum andglucomannan; and the like. Preferably the gelling agent comprises apolymer selected from the group consisting of hydroxypropyl cellulose,methylcellulose, hydroxypropylmethyl cellulose, polyethylene oxide,sodium carboxymethyl cellulose, sodium alginate and carrageenan.

Polyethylene oxide has been found to be particularly useful in thecomposition of the invention by virtue of its ability to gel quickly andto form a diffuse viscous mass inhibiting extraction of thepharmaceutically active ingredient. Preferably the PEO used has anaverage molecular weight of from 750,000 to 7,500,000, more preferablyfrom about 1,000,000 to about 6,500,000.

The gelling agent may be granulated to produce granules which can thenbe coated. Alternatively, the gelling agent-containing beads may bebuilt up on a core/substrate using powder-dosing or spray applicationtechniques known in the art. The core may be an “inert” core, in thesense that its sole function is to act a substrate upon which to buildthe beads (for example nonpareils or sugar spheres, microcrystallinecellulose spheres and the like). Alternatively the core may be made of amaterial which serves an additional purpose as well as acting as asubstrate (for example the core may be made of a buffering agent such astartaric acid).

Where an inert core is used as a substrate for the gellingagent-containing-beads the gelling agent may be applied to the inertcore in any suitable form. For example it may be applied as a powder oras a suspension or solution of the gelling agent in a suitablemedium/solvent. Preferably the gelling agent is incorporated into thegelling agent-containing beads in the form of a powder.

Typically the gelling agent-containing beads may be built up by applyingthe gelling agent to the core for subsequent coating. The use of aninert core in the gelling agent-containing beads is preferred when asimilar approach is used for producing the active ingredient-containingbeads (i.e. applying a layer of active ingredient to an inert core)—thisis because it may be difficult to match the shape and size of gellingagent-containing beads produced by a granulation approach to the shapeand size of active ingredient-containing beads produced using the inertcore approach. Typically substrate/nonpareil seeds having an averagediameter of 0.5-0.6 mm, 0.6-0.71 mm or 0.71-0.85 mm may be used. Avisible distinction between the active ingredient beads and the gellingagent beads that would enable the different types of beads to bedistinguished and separated should be avoided.

In order to further enhance hydration and gelling it may be advantageousfor the gelling agent to be present in particulate form (i.e. asdiscrete particles, such as a powder), as opposed to being present as afilm. When the gelling agent in the second bead population is present inthe form of particles the gelling agent applied to a substrate, thebeads may further comprise a binder to aid adhesion of the gelling agentto the substrate. The binder may also reduce possible hydration of thegelling agent during the manufacturing process, thus helping to maintainthe discrete particulate nature of the gelling agent and the hydrationaction of the final beads. The binder may suitably be selected from thegroup consisting of disaccharides, such as sucrose and lactose;polysaccharides, such as starch and microcrystalline cellulose; sugaralcohols, such as sorbitol and xylitol. Preferably the binder isselected from the group consisting of hydroxypropyl cellulose,hydroxypropyl methyl cellulose and polyvinyl pyrrolidone. A particularlypreferred binder is povidone (polyvinyl pyrrolidone), such as that soldunder the trade mark Kollidon (BASF SE) for example “Kollidon K30”. Thebinder, if present, may be used in any amount that successfully bindsthe gelling agent to the substrate. When used, the binder is typicallypresent in an amount of from 1 to 25% of the dry weight of gelling agentpresent, and preferably in an amount of from 10 to 15% of the dry weightof gelling agent. When a binder is used it is preferably applied to thesubstrate as a solution simultaneously with application of the gellingagent powder. Preferably the solvent used to form the binder solutioncomprises little or no water, thus minimising hydration or dissolutionof the gelling agent. Suitable solvent systems for use in application ofthe binder include isopropyl alcohol and isopropyl alcohol/watermixtures having a water content of 30% (by volume) of less. A preferredbinder solution is povidone (from about 1 to about 10% w/w) in a 5:1isopropyl alcohol/water mixture.

Preferably the gelling agent-containing beads comprise an inert core,such as sugar spheres, supporting a gelling agent, such as polyethyleneoxide (PEO), coated with a semi-permeable coating, such as an ammoniomethacrylate copolymer or a methacrylic acid copolymer. PEO may hydrateand disperse more quickly when in the form of aggregated particles asopposed to when it is formed as a film or compressed into a tablet.Furthermore, particulate PEO may facilitate the formation of a dispersedor diffuse gel. Accordingly, the polyethylene oxide is preferablypresent as a layer of PEO particles between the inert core and thesemipermeable coating. One embodiment of such a gelling agent-containingbead is shown schematically in FIG. 1. The gelling agent-containing bead(1) comprises a substrate (2) preferably made of an inert material thesole function of which is to act as a foundation to support the otherelements of the bead. The gelling agent (3) is applied to the substrate(2), preferably in particulate form (e.g. a polyethylene oxide powder).This may be achieved by applying a powder of the gelling agent, on tothe substrate (2). If a binder is being used it may be applied in theform of a solution (in a suitable solvent) simultaneously with theapplication of the gelling agent. The permeable or semi-permeablecoating (4) is then applied over the gelling agent layer (3).

Preferably an oral pharmaceutical composition of the inventioncomprising a second bead population wherein the gelling is particulatepolyethylene oxide and wherein the coating, comprises an ammoniomethacrylate copolymer and/or a methacrylic acid copolymer, furthercomprises povidone. The povidone acts as a binder further facilitatingand enhancing the gelling action of the beads.

The gelling agent may suitably be present in any amount that causes thecomposition to gel upon exposure to water to the extent that theviscosity of the composition mixed with a small amount of water (forexample 0.5 to 10 mL at 20° C.) prevents the mixture from being drawn upinto a syringe (for example an 18 gauge (1.270 mm diameter) needle).Preferably the gelling agent is present in an amount which does notcause any handling problems during manufacture of the composition (suchas clogging of coating, encapsulation or tableting equipment). Where thecomposition is presented in a capsule the gelling agent may be presentin amount of at least 15% (w/w) of the combined dry weight of activeingredient(s) and excipients present (in other words 15% w/w) of theoverall dry weight of composition), or at least 20 mg, preferably atleast 30 mg per capsule.

The coating applied to the gelling agent is a permeable orsemi-permeable coating. Suitable permeable and semi-permeable coatingmaterials are known in the art. These include for example cellulosicpolymers, such as cellulose acetates, cellulose alkanylates andcellulose acrylates; polyamides; polyurethanes; sulfonated polystyrenes;ammonio methacrylate copolymers such as poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1(for example those sold under the trade name Eurdgit® RS (EvonikIndustries AG); and methacrylic acid copolymers such as poly(methacrylicacid-co-ethyl acrylate) 1:1 (those sold under the trade name (Eudragit®L (Evonik Industries AG)). Preferably the coating comprises an ammoniomethacrylate copolymer or a methacrylic acid copolymer or a mixture ofthe foregoing.

The level of coating applied to the beads can be characterised in termsof weight gain (i.e. the weight of material applied to the uncoatedbeads) or in terms of coating thickness. From a manufacturingperspective coating to a specified weight gain is more practical as thiscan be more readily determined and controlled in-process.

When expressed in terms of weight gain, the coating may be characterisedin terms of the weight of polymer(s) only applied, or in terms of theweight of polymer solution/suspension (which may contain excipients suchas pore formers, anti-adherents etc in addition to the polymer(s)). Thecoating may suitably be present in an amount of about 5% to about 50%polymer weight gain (i.e. polymer weight added expressed as a percent ofthe weight of uncoated beads; excluding weight of any excipients addedwith the polymer). When the coating comprises an ammonio methacrylatecopolymer or a methacrylic acid copolymer, or a mixture thereof, thecoating is preferably applied to a polymer weight gain of from about7.5% to about 25%.

The coating level may also be characterised in terms of coatingthickness. However, as will be appreciated by the skilled person theuncoated beads are not perfect spheres and coating materials are notapplied with perfect uniformity across the entire surface of all beads.Therefore, coating thickness may vary somewhat across different areas ofany given bead and also from one bead to the next. Any coating thicknesswhich forms robust, separable beads and which facilitates ingress ofwater and hydration of the gelling agent will suffice for the purposesof the invention. Preferably the coating will have a thickness fromabout 1 to about 100 μm (microns). When the coating comprises an ammoniomethacrylate copolymer or a methacrylic acid copolymer the coating ispreferably applied to a thickness of about 10 to about 50 μm.

As will be appreciated by the skilled person, the coating may furthercomprise excipients designed to control the permeability of the coatingand/or the processing characteristics of the coating. For example, thecoating may further comprise one or more excipients selected from thegroup consisting of pore formers, plasticisers, lubricants, glidants andanti-adherent agents and the like.

The coating may comprise a water soluble pore former to aid permeabilityand thus facilitate hydration of the gelling agent. Suitable poreforming agents include hydroxypropyl methyl cellulose or othercellulosic derivatives, polyvinyl alcohol (PVA), polyethylene glycol(PEG), PVA-PEG copolymers, copovidone and the like. Mixtures of two ormore pore formers may be employed. The use of a pore former may beparticularly advantageous if a pH dependent coating is used. Some pHdependent coatings, such as enteric coatings, typically remainintact—preventing ingress of water—until exposed to a particular pH. Insuch a scenario the lack of permeability may be addressed by theaddition of a pore former, thus imparting a suitable degree ofpermeability to an otherwise impermeable coating. If present in thecomposition the pore former may typically be used in an amount of from 1to 20% w/w of the dry weight of coating polymer/material employed.

Where the coating comprises a plasticiser suitable plasticisers includefor example phthalates, such as alkyl or dialkyl phthalates includingdimethyl phthalate, ethyl phthalate, diethyl phthalate, and dibutylphthalate; citrates including triethyl citrate and acetyl triethylcitrate; and other plasticisers known in the art such as dibutylsebacate, triacetin and the like. When the coating comprises an ammoniomethacrylate copolymer or a methacrylic acid copolymer or a mixturethereof particularly preferred plasticisers are those selected from thegroup consisting of diethyl phthalate, dibutyl phthalate, triethylcitrate and dibutyl sebacate. When present, the plasticiser maytypically be used in an amount of from about 10 to about 30% (w/w) ofthe polymer applied.

The nature of the coating on the gelling agent-containing beads is suchthat the composition of the invention is adapted to expose the gellingagent to water (or some other liquid from its surrounding environment)in a controlled fashion when the composition is used intact and asintended.

Without wishing to be bound by any particular theory it is thought thatwhen the intact second bead population is exposed to water (or someother liquid) the permeable or semi-permeable nature of the coatingenables some water to pass through the coating, thus initiatinghydration of the gelling agent. When the resultant swelling of thegelling agent can no longer be contained by the coating, the coatingcracks or fractures facilitating further hydration. Upon furtherhydration the coating may breakdown to the extent that some of thegelling agent is released into the nearby vicinity. It is thought thatdispersal of the gelling agent in this manner leads to the formation ofa more diffuse, substantially uniform, gel compared to the situationwhere a gelling agent is presented in the form of a compacted mass, suchas in a tablet. If the composition is tampered with exposure of thegelling agent to water may occur in a more rapid and less controlledmanner. In either case the presence of the gelling agent-containingbeads functions to deter or prevent extraction of the active ingredientin a form that may be abused.

When the composition (either intact or crushed) is mixed with arelatively small volume of water a viscous mass is formed which makes itextremely difficult, if not impossible, for any of the pharmaceuticallyactive ingredient to be drawn up into a syringe. It is particularlyadvantageous for the composition to comprise a quantity of gelling agentwhich takes up substantially all of the volume of water required todissolve and extract the amount of active ingredient present. Forexample, the composition may comprise a quantity of gelling agent whichwill take up or absorb the minimum volume of water required to dissolvesubstantially all of the active ingredient present in the composition.In this way no supernatant will remain above the viscous mass (a stronggel) formed upon gelling of the gelling agent. In other words, therewill be no residual solution of the drug which could be filtered ordecanted off in order to separate it from the viscous material.Preferably, the composition comprises a quantity of gelling agentsufficient to ensure that when the composition is mixed (e.g. stirred orshaken at 20° C. and then left to sit for 10 min) with from about 1 toabout 10 mL of water no supernatant is formed i.e. substantially theentire volume of water is absorbed by the gelling agent in the formationof a viscous mass leaving no residual, separable active ingredientsolution.

On the other hand, attempting to extract the active ingredient by mixingthe composition (either intact or crushed) with a relatively largevolume of water, with a view to dissolving the active ingredient andseparating it from the remaining constituents by decanting orfiltration, produces a larger, more dispersed viscous mass (a weak gel),entrapping at least some the drug (for example undissolved drug whichmay still be present as intact drug-containing beads—particularly ifthere is a controlled release (CR) component in the composition). Anygiven amount of gelling agent may have a finite capacity to take up,hold or absorb water. If a sufficiently large volume of water is usedand this threshold is passed, then a supernatant may form. If acomposition of the invention is mixed with a relatively large volume ofwater, exceeding the capacity of the quantity of gelling agent present,and if the composition comprises an immediate release (IR) component,then at least some of the IR portion of active ingredient may bedissolved in the supernatant. However, even in a scenario where thesupernatant may be separable from the viscous material, the compositioncan be adapted such that the active ingredient solution thus recoveredwill be much too dilute and of such a low strength (in terms of drugconcentration) for it to produce a “high” were it to be injected.Accordingly, the invention provides a dosage form comprising a firstpopulation of beads and a second population of beads; said first beadpopulation comprising a pharmaceutically active ingredient susceptibleto, or having the potential for, abuse; and said second bead population(containing no pharmaceutically active ingredient) comprising a gellingagent and a permeable or semi-permeable coating; wherein, said firstbead population and said second bead population are physicallyseparable, but visually indistinguishable to the naked eye; and whereinless than about 25% (w/w) of the active pharmaceutically activeingredient is extracted from the composition after placing the dosageform in 100 mL of water for 30 min at 20° C.

In one preferred embodiment the pharmaceutically active ingredientcontained in the first population of beads is hydrocodone, or apharmaceutically acceptable salt thereof, and the second population ofbeads comprises polyethylene oxide, povidone (polyvinyl pyrrolidone) anda polymer selected from the group consisting of an ammonio methacrylatecopolymer, a methacrylic acid copolymer and a mixture thereof.

The present invention provides an oral pharmaceutical compositioncomprising a first population of beads and a second population of beads;said first bead population comprising a pharmaceutically activeingredient susceptible to, or having the potential for, abuse; and saidsecond bead population comprising a gelling agent and a permeable orsemi-permeable coating, but containing no pharmaceutically activeingredient; wherein, said first bead population and said second beadpopulation are physically separable, but visually indistinguishable tothe naked eye. In other words, an oral pharmaceutical compositioncomprises at least one active ingredient-containing component (the firstbead population as described above) and a component devoid of anypharmaceutically active ingredient (the second, gellingagent-containing, bead population as described above). However, in orderto manipulate the amount of drug present and the release profile, thecomposition may contain multiple active ingredient containingconstituents.

For example, the active ingredient-containing component may comprisemore than one population of active ingredient containing beads, witheach of such populations being adapted to release the drug in adifferent manner or at a different rate. The composition may comprise animmediate release active ingredient-containing population of beads whichrelease the drug upon administration, without any delay, and acontrolled release active ingredient-containing population of beadswhich is adapted to release the drug in a manner which is not immediate(e.g. delayed release, sustained release or some other form of modifiedor controlled release). The controlled or sustained release componentmay be modified so as to provide a lag or delay following administrationbefore the drug is released. Such a lag or delay may be achieved bycoating the active ingredient-containing beads with a controlled releasecoating known to the skilled person. In this manner two or more pulsesof drug release may be incorporated into the composition, thus providingflexibility in designing an appropriate overall release profile.

An oral pharmaceutical composition of the invention may compriseimmediate release active ingredient-containing beads, controlled releaseactive ingredient-containing beads, and gelling agent-containing beads;wherein said immediate release and said controlled release beadscomprise a pharmaceutically active ingredient susceptible to, or havingthe potential for, abuse; and said gelling agent-containing beadscomprise a gelling agent, but containing no pharmaceutically activeingredient; wherein, the various bead populations are each physicallyseparable, but visually indistinguishable to the naked eye.

A multiparticulate modified release hydrocodone bitartrate compositionis described in US 2006-0240105 A1 ((“the '105 publication”—the entirecontents of which are incorporated herein by reference) see inparticular Example 3; paragraphs [0099] to [0106], including Tables 6 to11). An oral morphine multiparticulate composition is disclosed U.S.Pat. No. 6,066,339 ((“the '339 patent”—the entire contents of which areincorporated herein by reference) see in particular Examples 1 to 6;columns 7 to 15, including the tables therein). Multiparticulatemodified release compositions are disclosed in U.S. Pat. No. 6,228,398((“the '398 patent”—the entire contents of which are incorporated hereinby reference) see in particular Examples 1 and 2 and the accompanyingtables and figure). A composition of the present invention may beproduced by combining a gelling agent-containing population of beadshaving a semi-permeable coating to the multiparticulate modified releasecomposition of the '105 publication, the '399 patent or the '398 patent.

Alternatively, immediate release and controlled release of activeingredient may be combined in a single bead population. This may beachieved by providing a drug containing core coated with a controlledrelease coating (the controlled release component) which is in turncoated with a layer of drug (the immediate release component). Uponadministration the outer drug layer is released immediately whilstrelease of drug from the coated core is modified according to thecharacteristics of the controlled release coating. Again, in this mannertwo or more pulses of active ingredient may be incorporated into thecomposition, thus providing flexibility in designing an appropriateoverall drug release profile.

The composition of the invention may comprise one or morepharmaceutically active ingredients. Where the composition comprises aplurality of active ingredients said active ingredients may be presentin the same population or separate populations of activeingredient-containing beads.

The composition of the invention comprising pharmaceutically activeingredient-containing beads and coated gelling agent beads as describedabove may be processed into a finished dosage form, for example byfilling a mixture of the various bead populations in the desiredproportions into a capsule. The beads are released from the capsule uponadministration to a subject. Depending on the dosage strength and volumeof the composition to be used the capsule size may range for examplefrom a size 5 capsule to a size 000. In terms of patient acceptabilityit is preferable that the composition be filled into a capsule no biggerthan a size 0E (elongated size 0) or a size 00. Alternatively, thecomposition may be processed into tablet form by compressing the blendedbeads into tablets. Where the composition is to be incorporated into atablet the various beads may be compressed together with a binder and/orhardening agent commonly employed in tableting such as microcrystallinecellulose (e.g. that sold under the trade mark Avicel® (FMCCorporation)) or a co-crystallised powder of maltodextrin and sucrose(e.g. that sold under the trade mark Di-Pac® (American Sugar Refining,Inc)). Upon administration to a subject the tablet disintegrates torelease the beads contained therein into the GI tract, thus exposingthem to GI fluids.

Where the composition comprises hydrocodone or a pharmaceuticallyacceptable salt thereof, such as hydrocodone bitartrate, said activeingredient is preferably present in an amount from 5 to 250 mg per unitdosage form.

In one embodiment an oral pharmaceutical composition comprises a firstpopulation of beads and a second population of beads; said first beadpopulation comprising hydrocodone or a pharmaceutically acceptable saltthereof; and said second bead population, free from pharmaceuticallyactive ingredient(s), comprising polyethylene oxide, povidone and apolymer selected from an ammonio methacrylate copolymer, a methacrylicacid copolymer or a mixture thereof. The hydrocodone or pharmaceuticallyacceptable salt may be the sole pharmaceutically active ingredientpresent in the composition. Preferably the first bead populationcomprises hydrocodone bitartrate in an amount from 5 to 250 mg.

In one embodiment an oral pharmaceutical composition comprises apopulation of immediate release hydrocodone bitartrate beads, apopulation of controlled release hydrocodone bitartrate beads and apopulation of gelling agent-containing beads; said gellingagent-containing beads comprising polyethylene oxide, povidone and apermeable or semi-permeable coating material selected from an ammoniomethacrylate copolymer, a methacrylic acid copolymer or a mixturethereof, but containing no pharmaceutically active ingredient.Preferably the immediate release beads contain from 1 to 75% w/w of thetotal amount of hydrocodone bitartrate in the composition and thecontrolled release beads contain the remainder i.e. the controlledrelease beads contain from 25 to 99% w/w of the total amount ofhydrocodone bitartrate in the composition.

The invention provides a dosage form comprising a composition accordingas described above wherein the gelling agent is present in eachindividual dosing unit (e.g. each capsule or tablet) in an amountsufficient to form an abuse deterring gel when the dosage form is mixedwith or added to 1 to 100 mL of water. Typically the gelling agent ispresent in each individual dosing unit in an amount of at least about 20mg (per unit), preferably in an amount of at least 30 mg (per unit). Theupper limit of the amount of gelling agent that may be used isdetermined by a combination of the size of the activeingredient-containing beads and the size of the dosage form (i.e.capsule or tablet). Whilst in general it is preferable for thecomposition to comprise as much gelling agent as possible, this isbalanced by the need for the gelling agent-containing beads to match theactive ingredient beads in size and appearance so as to preventseparation of the different bead populations. Furthermore, the overallsize of the capsule or tablet into which the composition is incorporatedwill place a limit on the amount of gelling agent-containing beads thatcan be used. Preferably the gelling agent is present in each individualdosing unit in an amount from 20 to 500 mg (per unit). Preferably thegelling agent is present in an amount sufficient to provide a gellingagent/active ingredient ratio for the composition of from 1:10 to 10:1.

Gelling agent-containing beads for use in the present invention may beprepared according to the following general method:

-   -   (a) The gelling agent (together with the binder, if any) is        applied to a core using a fluid bed processor, to form uncoated        gelling agent beads;    -   (b) The coating material (together with any glidant and other        excipients, if any) is then applied to the uncoated beads        obtained from the previous step using a fluid be processor, to        form coated gelling agent beads having a coating of the desired        weight gain or thickness; and    -   (c) The coated beads obtained from the previous step are then        dried, typically for a period of about 12 to 24 hours and a        temperature of about 30 to 50° C., to form finished gelling        agent-containing beads.

The finished beads may optionally be screened to separate beads of adesired particle size (diameter).

The gelling agent-containing beads (which contain no pharmaceuticallyactive ingredient) may be blended with active ingredient-containingbeads to form a blend which may be filled into capsules or compressedinto tablets. Alternatively, in the case of a capsule presentation,gelling agent-containing beads of the invention may be added to thecapsule separately, either before or after other components of thedosage form. Active ingredient-containing beads may be preparedaccording to processes known in the art, such as those disclosed in U.S.Pat. No. 6,066,339, U.S. Pat. No. 6,228,398 or US 2006-0240105 A1 forexample (the entire contents of each of which are incorporated herein byreference).

Depending on the dosage strength, the dosage form and the relativeproportions of the different bead populations present, the amounts ofthe various constituents in the composition may vary. Some exemplaryformulations for abuse resistant compositions according to theinvention, indicating typical ranges for the amount of each componentpresent, are shown in Table (i).

TABLE (i) Abuse resistant compositions. Range Material (% w/w)Pharmaceutically active ingredient(s)  1.0-20.0 Bead substrate (e.g.sugar spheres) 35.0-60.0 Controlled release polymer(s)  2.5-25.0Glidant(s)/anti-adherant(s) 0.5-7.5 Gelling agent(s) 15.0-45.0 Binder(s)1.0-5.0

Further details of how to prepare compositions according to theinvention are set out in the Examples below.

The present invention also relates to methods of treatment based on theabuse resistant oral pharmaceutical compositions described above.Accordingly, the invention provides a method of treating a subject inneed of treatment with a pharmaceutically active ingredient susceptibleto, or having the potential for, abuse comprising the step ofadministering to said subject an effective amount of an oralpharmaceutical composition comprising a first population of beads and asecond population of beads; said first bead population comprising thepharmaceutically active ingredient susceptible to, or having thepotential for, abuse; and said second bead population comprising agelling agent and a permeable or semi-permeable coating, but containingsubstantially no pharmaceutically active ingredient.

A preferred method of the invention is a method for the treatment ofpain comprising administering to a subject in need thereof a compositionas described above wherein said first population of beads comprises ananalgesically effective amount of a pharmaceutically active ingredientselected from the group consisting of hydrocodone, hydrocodonebitartrate,17-(cyclobutylmethyl)-4,14-dihydroxy-6-oxo-morphinan-3-carboxamide,(4bR,8aS,9R)-11-(cyclobutylmethyl)-4,8a-dihydroxy-6-oxo-6,7,8,8a,9,10-hexahydro-5H-9,4b-(epiminoethano)phenanthrene-3-carboxamideand pharmaceutically acceptable salts of the foregoing. Preferably wherethe pharmaceutically active ingredient used in the foregoing method ishydrocodone or a pharmaceutically acceptable salt thereof, said activeingredient is present in an amount of between 5 and 250 mg per unitdosage form. In a particularly preferred embodiment, the method of theinvention comprises administering a composition comprising between 5 and250 mg of hydrocodone or a pharmaceutically acceptable salt thereof,wherein said hydrocodone or said pharmaceutically acceptable saltthereof is the sole pharmaceutically active ingredient present in thecomposition.

EXAMPLES

The source of various materials and equipment is indicated throughoutthe Examples. Where a source is not indicated the material or equipmentwould be readily available to the skilled person.

In the Examples that follow: “EP” means European Pharmacopeia; “NF”means National Formulary; and “USP” means US Pharmacopeia.

Example 1 1.1 Polyethylene Oxide Beads

Abuse deterrent beads for use in compositions according to the inventionwere prepared using the materials set out in Table 1.1 below.

TABLE 1.1 Composition of gelling agent-containing, abuse deterrentbeads. Material Amount Amount (Type/Grade) (mg/g) (% (w/w)) Polyethyleneoxide (Polyox ® WSR^([1]) 443.9 44.39 coagulant LEO, NF) Povidone(K30^([2]), USP) 45.5 4.55 Sugar spheres (30/35 mesh, NF) 317.0 31.70Eudragit ® RS (ammonio methacrylate 96.8 9.68 copolymer Type B^([3]), NFEP) Silicon dioxide (Syloid ® 244^([4]) 48.4 4.84 FP, NF) Talc (USP EP)48.4 4.84 Total 1,000.0 100.00 ^([1])The Dow Chemical Company - Midland,MI, USA; ^([2])Sigma-aldrich Corp. - St. Louis, MO, USA; ^([3])EvonikIndustries AG, Essen Germany; ^([4])WR Grace & Co. - Columbia, MD, USA.

The abuse deterrent beads were manufactured as follows:

-   -   A binder solution containing the povidone dissolved in isopropyl        alcohol and water* (20% by weight H₂O in IPA) was prepared.    -   The ammonio methacrylate copolymer was dissolved in a mixture of        isopropyl alcohol, acetone and water (78.0%/16.6%/5.4% by weight        i.e. IPA:acetone:ratio of 14.44:3.04:1)) to form a 5.5% w/w        polymer solution.    -   A glidant blend was prepared by bag blending the silicon dioxide        and talc.    -   The binder solution and polyethylene oxide (powder; having an        average molecular weight of approx. 5,000,000) were then        simultaneously applied onto 30/35-mesh sugar spheres using a        Vector Granurex GX-40 rotor processor (Freund-Vector        Corp.—Marion, Iowa, USA). The Granurex process parameters used        were as follows—slit air temperature: 25-42° C.; slit air flow:        10-30 cfm; rotor speed: 180-205 rpm; binder solution spray        rate**: 13-56 g/min; PEO powder feed rate**: approx. 6-48 g/min.    -   The coating suspension and glidant blend were then applied to        thepolyethylene oxide layered sugar spheres forming abuse        deterrent beads using a Vector Granurex GX-40 rotor processor        (Freund-Vector Corp.—Marion, Iowa, USA). The process parameters        for applying the coating were as follows—slit air temperature:        42° C.; slit air flow: 30 cfm; rotor speed: 250 rpm; coating        solution spray rate; powder feed rate: 2.0 g/min.    -   The abuse deterrent beads were dried in a temperature and        humidity-controlled oven (flatbed tray oven) for 20 hours at 40°        C./50%RH (relative humidity) to reduce residual solvent and        stabilize any moisture content.    -   After drying, the beads were collected and screened using a        Russell Finex sieve shaker (Russell Finex Limited—Fletham,        Middlesex, United Kingdom) to separate oversize material        (retained on a 16-mesh sieve) and fines (through a 40-mesh        sieve), if any, formed during the process.        -   (* The solvents mentioned are driven off during the            manufacturing process and/or during drying and are not            incorporated into the end product to any significant            degree.)        -   (** The solution spray rate and the powder feed rate were            ramped up in tandem as the batch progressed.)

1.2 Hydrocodone Bitartrate Immediate Release Beads

Hydrocodone bitartrate immediate release (IR) beads having thecomposition set out in Table 1.2 were prepared as described below.

TABLE 1.2 Composition of hydrocodone bitartrate immediate release beads.Material Amount Amount (Type/Grade) (mg/g) (% (w/w)) Hydrocodonebitartrate (USP)^([5]) 200.0 20.00 Sugar spheres (30/35 mesh, NF) 683.368.33 Silicon dioxide (Syloid ® 244 FP, NF) 66.7 6.67 Hypromellose 2910(6 cPs, USP) 50.0 5.00 Total 1,000.0 100.00 ^([5])Noramco, Inc - Athens,GA, USA

The hydrocodone bitartrate IR beads were manufactured as follows:

-   -   A solution containing 1.5% w/w hypromellose and 6.0% w/w        hydrocodone bitartrate dissolved in water was prepared.    -   2.0% w/w silicon dioxide was added to the solution formed in the        previous step and mixed to form an immediate release coating        solution.    -   The IR coating solution was then applied onto 30/35-mesh sugar        spheres using a Glatt® GPCG fluid bed system (Glatt air        Techniques, Inc—Ramsey, N.J., USA) equipped a Wurster insert.    -   After application of the active to the sugar spheres, the        resultant IR beads were dried for approximately 10 minutes in        the fluid bed and cooled before discharge.    -   The discharged beads were then screened using a Russell Finex        sieve shaker to separate oversize (retained on a 20-mesh sieve)        and fines (through a 35-mesh sieve), if any, formed during the        process.

The screened beads produced according to the above process were eitherused as IR beads or processed further to produce SR beads as set outbelow.

1.3 Hydrocodone Bitartrate Controlled Release Beads—1

As described below hydrocodone bitartrate IR beads as described abovewere coated with a pH independent polymer coating to produce controlledrelease (CR) beads having the composition set out in Table 1.3.

A coating suspension was prepared as follows:

-   -   The ammonio methacrylate copolymer type B (Eudragit® RS) was        dissolved in a mixture of isopropyl alcohol, acetone, and water        (78.0:16.6:5.4).    -   Talc and silicon dioxide (0.83% w/w in each case) were added to        the solution from the previous step as anti-adherents to prevent        agglomeration of the beads during coating.

The CR coating suspension was applied onto immediate release beads asprepared above in section 1.2 using a Glatt GPCG fluid bed systemequipped with a Wurster insert.

TABLE 1.3 Composition of hydrocodone bitartrate controlled releasebeads. Material Amount Amount (Type/Grade) (mg/g) (% (w/w)) Hydrocodonebitartrate (USP) 179.0 17.90 Sugar spheres (30/35 mesh, NF) 611.6 61.16Hypromellose 2910 (6 cPs, USP) 44.8 4.48 Eudragit ® RS (ammoniomethacrylate 80.6 8.06 copolymer Type B, NF EP) Silicon dioxide(Syloid ® 244 FP, NF) 71.8 7.18 Talc (USP EP) 12.2 1.22 Total 1,000.0100.00

Coating was performed until a polymer weight gain of 9% was achieved.After the target weight was applied, the CR beads were dried forapproximately 10 minutes in the fluid bed and cooled before discharge.Coated beads were then dried in a temperature and humidity-controlledoven for 20 hours at 40° C./50%RH. After drying, the beads werecollected and screened using a Russell Finex sieve shaker to separateoversize (retained on a 20-mesh sieve) and fines (through a 35-meshsieve), if any, formed during the process.

1.4 Hydrocodone Bitartrate Controlled Release Beads—2

Controlled release beads having the composition set out in Table 1.4were prepared.

The coating suspension comprising a pH dependent polymer was prepared asfollows:

-   -   Methacrylic acid copolymer Type A (Eudragit® L) (6.25% w/w) and        triethyl citrate (12.5% w/w) were dissolved in a mixture of        isopropyl alcohol, acetone and water (78.0:16.6:5.4).    -   Talc and silicon dioxide (0.94% w/w in each case) were added to        the solution from the previous step as anti-adherents to prevent        agglomeration of the beads during coating.

The coating suspension was applied to CR beads described above insection 1.3 to a polymer weight gain of 20% using a similar procedure tothat described in section 1.3.

TABLE 1.4 Alternate composition of hydrocodone bitartrate sustainedrelease beads. Material Amount Amount (Type/Grade) (mg/g) (% (w/w))Hydrocodone bitartrate (USP) 137.7 13.77 Sugar spheres (30/35 mesh, NF)470.4 47.04 Hypromellose 2910 (6 cPs, USP) 34.4 3.44 Eudragit ® RS(ammonio methacrylate 62.0 6.20 copolymer Type B, NF EP) Silicon dioxide(Syloid ® 244 FP, NF) 78.4 7.84 Talc (USP EP) 32.5 3.25 Eudragit ® L(methacrylic acid 153.8 15.38 copolymer Type A^([6]), NF EP) Triethylcitrate (NF) 30.8 3.08 Total 1,000.0 100.00 ^([6])Evonik Industries AG,Essen Germany

The hydrocodone IR and CR beads may be mixed in different proportionsand filled into capsules to provide dosage forms having differentstrengths and release profiles.

Example 2

A composition of the invention, Composition 1 (summarized in Table 2.1below), was prepared by blending IR beads as described in section 1.2and CR beads as described in section 1.3, in a ratio of 20:80 (IR:CR)based on hydrocodone bitartrate content and filling the resultant blendinto size 0 hard gelatin capsules along with 75 mg of PEO beads asdescribed in section 1.1 to produce compositions having a strength of 20mg/capsule.

TABLE 2.1 Hydrocodone bitartrate Composition 1 (per capsule). MaterialComposition 1 (Type/Grade) Amount (mg) Hydrocodone bitartrate (USP) 20.0Sugar spheres (30/35 mesh, NF) 92.1 Hypromellose 2910 (6 cPs, USP) 5.0Eudragit ® RS (ammonio methacrylate 14.5 copolymer Type B, NF EP)Silicon dioxide (Syloid ® 244 FP, NF) 11.4 Talc (USP EP) 4.7Polyethylene oxide (Polyox ® WSR 33.3 coagulant LEO, NF) Povidone (K30,USP) 3.4 Total 184.4

A comparator composition, Composition 2 (summarized in Table 2.2), whichwas essentially the same as Composition 1, but with no gellingagent-containing bead component, was prepared by blending IR beads asdescribed in section 1.2 and CR beads as described in section 1.3 in aratio of 20:80 (IR:CR) based on active ingredient content and fillingthe resultant blend into size 0 hard gelatin capsules to producecompositions having a strength of 20 mg/capsule.

TABLE 2.2 Comparator Composition 2 (per capsule) Composition Material 2(Control) (Type/Grade) Amount (mg) Hydrocodone bitartrate (USP) 20.00Sugar spheres (30/35 mesh, NF) 68.34 Hypromellose 2910 (6 cPs, USP) 5.00Eudragit ® RS (ammonio methacrylate 7.20 copolymer Type B, NF EP)Silicon dioxide (Syloid ® 244 FP, NF) 7.76 Talc (USP EP) 1.08 Total109.38

Example 3

A composition of the invention, Composition 3 (summarized in Table 3.1below) was prepared by blending IR beads as described in section 1.2 andCR beads as described in section 1.4 in a ratio of 20:80 (IR:CR) basedon active ingredient content and filling the resultant blend into size 0hard gelatin capsules along with 75 mg of PEO beads as described insection 1.1 to produce compositions having a strength of 20 mg/capsule.

TABLE 3.1 Hydrocodone bitartrate Composition 3 (per capsule). MaterialComposition 3 (Type/Grade) Amount (mg) Hydrocodone bitartrate (USP) 20.0Sugar spheres (30/35 mesh, NF) 92.1 Hypromellose 2910 (6 cPs, USP) 5.0Eudragit ® RS (ammonio methacrylate 14.5 copolymer Type B, NF EP)Silicon dioxide (Syloid ® 244 FP, NF) 14.0 Talc (USP EP) 7.4 Eudragit ®L (methacrylic acid copolymer 17.9 Type A, NF EP) Triethyl citrate (NF)3.6 Polyethylene oxide (Polyox ® WSR 33.3 coagulant LEO, NF) Povidone(K30, USP) 3.4 Total 211.2

A comparator composition (Composition 4) which was essentially the sameas Composition 3, but with no gelling agent-containing bead component,was prepared by blending IR beads as described in section 1.2; and CRbeads as described in section 1.4 in a ratio of 20:80 (IR:CR) based onhydrocodone bitartrate content and filling the resultant blend into size0 hard gelatin capsules to produce compositions having a strength of 20mg/capsule.

Example 3

3.1 In vitro release profiles

FIG. 2 shows the in vitro release of hydrocodone bitartrate in phosphatebuffer (pH 6.8) from Compositions 1 and 3 and from the respectivecomparators (Compositions 2 and 4). Active ingredient concentrationswere determined by a validated HPLC method according to USP <711> usingthe following apparatus and conditions—USP Apparatus 1 (40-mesh basket);rotation: 100 rpm; timepoints: 1, 2, 4, 6, 8 and 12 hours; medium: 500mL pH 6.8 phosphate buffer; temperature: 37.0+/−0.5° C. Thecontrol/comparator compositions contain the same amount of activeingredient and were designed to release the hydrocodone at substantiallythe same rate as the respective composition according to the invention.The primary difference between the comparators and the compositions ofthe invention was the absence of a population of beads containing agelling agent in the former, the gelling agent (PEO) beads being a keyfeature of the latter (compositions of the invention). FIG. 2 shows thatthe in vitro release of drug from all four compositions is very similar.It is concluded from this data that the presence of the PEO beads inCompositions 1 and 3 did not impact the release of active ingredient.

3.2 In Vivo Release Profiles

Compositions 1 to 4 were administered orally as a single dose to healthyvolunteers in a human pharmacokinetic study. Plasma concentrations ofhydrocodone were determined at various time points post administration.

FIG. 3 shows mean plasma concentration levels following administrationof Composition 1 and Comparator Composition 2. FIG. 4 shows mean plasmaconcentration levels following administration of Composition 3 andComparator Composition 4. Various PK parameters for the fourcompositions are summarised in Table 3.1 below.

TABLE 3.1 Summary of pharmacokinetic parameters. (*Geometric mean ratioinvention vs. control) Composition AUC_((0-t))* C_(max)* T_(max) (hrs)T_(1/2) (hrs) 1 0.97 1.00 5 8.07 2 (Control) — — 6 8.69 3 1.09 1.09 67.07 4 (Control) — — 6 7.56

FIGS. 3 and 4 and Table 3.1 indicate that each pair of compositions (1 &2; 3 & 4) are substantially bioequivalent. In other words, on the basisof this data the presence of the PEO beads (in Compositions 1 and 3)does not impact on the in vivo release of hydrocodone bitartrate fromthe composition.

Example 4 Abuse Mitigation—Attempt to Extract and Syringe API UsingSmall Volume of Water

Compositions of the invention, Compositions 5 and 6, were prepared asset out below.

4.1 PEO Abuse Deterrent Beads

Polyethylene oxide powder (av. m. wt. approx. 5,000,000) was applied tosugar sphere cores together with a PVP binder solution. The resultantPEO beads were coated with a coating comprising an ammonio methacrylatepolymer (10% polymer weight gain). The binder solution, polymersuspension and overall content of the finished PEO beads are set outbelow in Tables 4.1 to 4.3 respectively. The methodology and processingparameters were substantially the same as those described in Example 1above.

TABLE 4.1 Binder solution Material (Type/Grade) Amount (mg/g) PVP(Povidone K30, USP) 84.5 Water 183.1 Isopropyl alcohol (USP) 732.4

TABLE 4.2 Coating suspension Material (Type/Grade) Amount (mg/g) Ammoniomethacrylate copolymer, 55.0 Type B (Eudragit RS; NF, EP) Acetone (NF,EP) 154.0 Isopropyl alcohol (USP) 724.4 Water 50.0 Silicon dioxide(Syloid ® 244 FP) 8.3 Talc (USP) 8.3

TABLE 4.3 Finished abuse deterrent beads Material (Type/Grade) Amount(mg/g) Sugar spheres (35/40 mesh, NF) 347.9 Polyethylene oxide (PolyoxWSR 487.0 coagulant LEO, NF) PVP (Povidone K30, USP) 50.0 Ammoniomethacrylate copolymer, 88.5 Type B (Eudragit RS; NF, EP) Silicondioxide (Syloid ® 244 FP) 13.4 Talc (USP) 13.4

4.2 Hydrocodone Bitartrate Capsules

Hydrocodone bitartrate compositions comprising 20% IR beads/80% CR beads(20:80 by active ingredient content) and an abuse deterrent componentwere prepared by blending PEO abuse deterrent beads (as per section4.1), hydrocodone bitartrate immediate release (as per section 1.2) andhydrocodone bitartrate controlled release beads (as per sections 1.3) toprovide the amounts shown in Table 4.4. Each blend was filled into hardgelatin capsules.

TABLE 4.4 Compositions 5 and 6 (*0EL or 0E - elongated size 0) Amount(mg/capsule) Material Composition 5 Composition 6 HydrocodoneBitartrate, USP 20.0 50.0 Sugar Spheres, NF 135.0 234.4 Hypromellose2910, (6 cps) USP 5.0 12.5 Eudragit RS, NF, EP 24.2 34.2 SiliconDioxide, NF (Syloid ® 244 FP) 10.3 21.8 Talc, USP 3.6 5.2 PolyethyleneOxide, NF (Polyox 93.3 89.0 WSR Coagulant LEO) Povidone K30, USP 9.6 9.1Total 301.0 456.2 Capsule size 0 0EL*

4.4 Abuse Resistance

The ability of a composition of the invention to deter attempts toproduce an injectable form of the active ingredient was investigated byadding the contents of a capsule of Composition 5 (20 mg hydrocodonebitartrate) and Composition 6 (50 mg hydrocodone bitartrate) to severalrelatively small volumes of water (1, 2 and 5 mL respectively). Thevolumes used were chosen as representative of the syringe volumes thatmay typically be used by someone attempting to abuse a composition ofthis type. Samples were shaken for 10 minutes and observations were madeat both ambient conditions and after samples had been placed in boilingwater for 5 minutes. A clearly visible, viscous mass was produced ineach case, see for example FIG. 5A (Composition 5; ambient conditions).With each of the three volumes investigated the gelling agent acted toabsorb the entire volume of water, leaving no supernatant above theviscous material.

The material produced could not be filtered, thus providing no filtrateupon which to test injectability. An attempt was made to directlysyringe the material produced when the composition is mixed with 1 mL ofwater (using an 18 gauge needle) was unsuccessful (see FIG. 5B). Theviscosity of the material was such that nothing could be drawn up intothe syringe.

Separating the active ingredient into small volumes of a suitablesolvent could potentially facilitate an attempt to directly inject theextract. The results of this Example illustrate the abuse mitigatingeffects of a composition according to the invention.

Example 5

This Example investigates the behaviour of compositions of theinvention, and a prior art comparator composition, when mixed with arelatively large volume of water. The intent being to simulate anattempt to extract the active ingredient from the respective dosageforms.

The methodology employed was as follows:

-   -   A single capsule of a hydrocodone bitartrate composition        according to the invention (Compositions 5 and 6) or a single        oxycodone tablet (see note [1] below), water (either 100 or 200        mL) and a magnetic stirring bar were placed in a glass flask        with a screw on lid.    -   A pION, Spectra Rainbow Dynamic model, fibre optic probe (Pion,        Inc—Billerica, Mass., USA) for determining the concentration of        active ingredient was passed through the lid and placed in        contact with the water. In the cases of both hydrocodone        bitartrate and oxycodone the drug substance concentration was        determined at 270-290 nm (20 mm path length, second derivative).    -   The stirring bar was activated and a timer was started.    -   The concentration of active ingredient was determined at various        time points.    -   Photographs of the flask and contents were taken at t=0 and t=60        min.

-   ([1] Oxycodone comparator consisted of Oxycontin® 30 mg and 80 mg    tablets. According to the package insert for Oxycontin®, apart from    oxycodone hydrochloride, each tablet contains the following inactive    ingredients: ammonio methacrylate copolymer, hypromellose, lactose,    magnesium stearate, polyethylene glycol 400, povidone, sodium    hydroxide, sorbic acid, stearyl alcohol, talc, titanium dioxide and    triacetin. The 30 mg tablets also contain: polysorbate 80, red iron    oxide, yellow iron oxide and black iron oxide. The 80 mg tablets    also contain: FD&C blue No. 2, hydroxypropyl cellulose and yellow    iron oxide. (Oxycontin® is a registered trade mark of Purdue Pharma    LP))

FIGS. 6 and 7 illustrate the behaviour of hydrocodone bitartratecompositions according to the invention (Composition 5, 20 mg strengthand Composition 6, 50 mg strength; in FIGS. 6 and 7 respectively) whenmixed with water (100 mL or 200 mL) and stirred for 60 minutes.

The contents of a capsule of Composition 5 were emptied out and added(unaltered) to 100 mL of water with stirring. With reference to FIG. 6A,it was observed that the water quickly started to turn turbid. Thethickening of the liquid phase was clearly visible. After one hour (FIG.6B) the entire volume of water had become cloudy and almost opaque. Nosupernatant was formed and the visual appearance of the entire volumewas uniform. The experiment was repeated with n=3 capsules, with similarresults observed each time.

Similar behaviour was observed when Composition 6 of the invention wasadded to 100 or 200 mL of water, see FIGS. 7A (t=0) and 7B (t=60 min).Again the experiment was repeated with n=3 capsules, with similarresults observed each time.

FIG. 8 (comparative example) shows what happens when an oxycodone tablet(Composition 7: Oxycontin, 30 mg—FIG. 8A; Composition 8: Oxycontin 80mg—FIG. 8B) comprising a gelling agent is added to water (100 mL) andstirred for 30 minutes.

In order to mimic the actions of a potential abuser, the Oxycontin®tablets were cut into six approximately equal sized pieces to expose theinterior portions of the dosage form. Upon addition of the tablet piecesto the water some gelling on the exposed surfaces was observed and someclouding of the water developed. At the one hour time point the tabletpieces were still clearly visible on the bottom of the flask. The liquidabove the tablet pieces was readily drawn off for analysis and no changein viscosity was apparent. The experiment was repeated with n=3Oxycontin® tablets, with similar results observed each time.

Qualitatively similar behaviour, as that seen with Oxycontin® tablets,was observed for polyethylene oxide based hydrocodone bitartratemini-tablets and extruded pellets.

The use of a fibre optic probe enabled the release of active ingredientto be followed without having to extract a sample from the test materialover the time period during which the photographs (FIG. 6A, 6B, 7A, 7B)were taken. The relative behaviour of the compositions of the inventiondepicted in FIGS. 6 and 7 and the prior art composition depicted in FIG.8 are illustrated by the data set out in Table 5.1 below and shown inFIG. 9.

TABLE 5.1 Amount of drug extracted from compositions of the inventionand two comparator compositions. (*Comparator compositions) Amount ofdrug in Percentage of label Composition solution (mg) claim (% (w/w)) 54.6 23.0 6 11.8 23.6  7* 19.9 66.2  8* 41.7 52.1

The data in Table 5.1 and FIG. 9 indicates that considerably more activeingredient was released from the comparator compositions (7 and 8). Therelease from the compositions of the invention corresponds to the 20% IRactive ingredient component of each composition. However, it should benoted that whilst this fraction of hydrocodone was released from thecomposition, the highly viscous and uniform nature of the gel producedin the entire volume of water used means that it would be extremelydifficult, if not impossible, for the release active ingredient to beseparated from the gel.

General Conclusions from the Examples

The gelling-agent component of the compositions of the invention doesnot adversely impact the in vitro or in vivo release of pharmaceuticallyactive ingredient from the composition (intact and not subjected to anytampering). In particular, the presence of the gelling agent-containingbeads does not have any adverse effect on the bioavailability of theactive ingredient.

Compositions of the invention exhibit a gelling behaviour when added towater, even in the absence of any tampering i.e. the composition behavesthe same whether the gelling agent-containing beads are added to waterintact or are crushed first. When mixed with a relatively small volumeof water a viscous mass is formed which cannot be drawn up into asyringe. This thwarts attempts to inject the entire contents of thecomposition.

On the other hand, attempting to extract the active ingredient by mixingthe composition with a relatively large volume of water (in order todissolve the drug and separate it from the remaining constituents bydecanting and/or filtering) produces a uniform, dispersed, viscous mass,entrapping any dissolved drug and any intact beads.

1-15. (canceled)
 16. A method for the treatment of pain comprisingadministering to a subject in need thereof a composition comprising afirst population and a second population of beads; the first populationof beads being substantially free of polyethylene oxide and beingselected from the group consisting of hydrocodone and pharmaceuticallyacceptable salt thereof, and the second population of beads beingsubstantially free of any pharmaceutically active ingredient andcomprising polyethylene oxide and a permeable or semi-permeable coatingselected from the group consisting of an ammonio methacrylate copolymer,a methacrylic acid copolymer and a mixture thereof.
 17. The method ofclaim 16, wherein said second population of beads further comprisespovidone.
 18. The method of claim 16, wherein the polyethylene oxide ispresent in particulate form.
 19. The method of claim 19, wherein theactive is hydrocodone bitartrate.
 20. The method of claim 16, whereinthe active is present in an amount of from 5 to 250 mg.